2. Academic Validation
  3. Inhibition of the E3 ligase UBR5 stabilizes TERT and protects vascular organoids from oxidative stress

Inhibition of the E3 ligase UBR5 stabilizes TERT and protects vascular organoids from oxidative stress

  • J Transl Med. 2024 Nov 28;22(1):1080. doi: 10.1186/s12967-024-05887-0.
Haijing Zhao # 1 2,  Nian Cao # 1,  Qi Liu # 2,  Yingyue Zhang 1 2,  Rui Jin 3,  Huiying Lai 4,  Li Zheng 5,  Honghong Zhang 1 2,  Yue Zhu 1 2,  Yuhan Ma 5,  Zengao Yang 6,  Zhengfeng Wu 1 2,  Weini Li 7,  Yuqi Liu 8 9 10 11,  Long Cheng 12 13,  Yundai Chen 14
Affiliations

Affiliations

  • 1 Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China.
  • 2 Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China.
  • 3 Beijing Institute of Biotechnology, Beijing, 100850, People's Republic of China.
  • 4 Department of Clinical Laboratory, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China.
  • 5 School of Medicine, Nankai University, Tianjin, 300071, People's Republic of China.
  • 6 School of Medicine, South China University of Technology, Guangzhou, 510006, People's Republic of China.
  • 7 Department of Biomedical Science, Cedars-Sinai Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
  • 8 Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China. ametuofo980869@163.com.
  • 9 National Key Laboratory of Kidney Diseases, Beijing, 100853, People's Republic of China. ametuofo980869@163.com.
  • 10 Department of Cardiology, National Clinical Research Center of Geriatric Disease, Beijing, 100853, People's Republic of China. ametuofo980869@163.com.
  • 11 Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Beijing, 100853, People's Republic of China. ametuofo980869@163.com.
  • 12 The Key Laboratory of Geriatrics, Institute of Geriatric Medicine, Beijing Institute of Geriatrics, Chinese Academy of Medical Sciences, Beijing Hospital/National Centre of Gerontology of National Health Commission, Beijing, 100730, People's Republic of China. biolongcheng@outlook.com.
  • 13 Beijing Institute of Biotechnology, Beijing, 100850, People's Republic of China. biolongcheng@outlook.com.
  • 14 Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China. cyundai@vip.163.com.
  • # Contributed equally.
PMID: 39609696 DOI: 10.1186/s12967-024-05887-0
Abstract

Background: Excessive oxidative stress is known to cause endothelial dysfunction and drive cardiovascular diseases (CVD). While telomerase Reverse Transcriptase (TERT) shows protective effects against oxidative stress in rodents and is associated to human flow-mediated dilation in CVD, its regulatory mechanisms in human vascular systems under pathological oxidative stress require further investigation.

Methods: Human induced pluripotent stem cells (hiPSCs) were used to create vascular organoids (VOs). These VOs and human umbilical vein endothelial cells (HUVECs) were subjected to oxidative stress through both hydrogen peroxide (H2O2) and oxidized low-density lipoprotein (oxLDL) models. The effects of TERT overexpression by inhibition of the ubiquitin protein Ligase E3 component N-recognin 5 (UBR5) on Reactive Oxygen Species (ROS)-induced vascular injury and cellular senescence were assessed using neovascular sprouting assays, senescence-associated β-galactosidase (SA-β-Gal) staining, and senescence-associated secretory phenotype (SASP) assays.

Results: ROS significantly impaired VO development and endothelial progenitor cell (EPC) angiogenesis, evidenced by reduced neovascular sprouting and increased senescence markers, including elevated SA-β-Gal activity and SASP-related cytokine levels. Overexpression of TERT counteracted these effects, restoring VO development and EPC function. Immunoprecipitation-mass spectrometry identified UBR5 as a critical TERT regulator, facilitating its degradation. Inhibition of UBR5 stabilized TERT, improving VO angiogenic capacity, and reducing SA-β-Gal activity and SASP cytokine levels.

Conclusions: Inhibiting UBR5 stabilizes TERT, which preserves EPC angiogenic capacity, reduces VO impairment, and delays endothelial cell senescence under oxidative stress. These findings highlight the potential of targeting UBR5 to enhance vascular health in oxidative stress-related conditions.

Keywords

Oxidative stress; Senescence; TERT; UBR5; Vascular organoids.

Figures
Products